Bioerodible ocular device

ABSTRACT

An ocular insert for the continuous controlled administration of a predetermined therapeutically effective dosage of drug to the eye over a prolonged period of time. The device meters the flow of drug by means of a drug release rate controlling material. The insert bioerodes in the environment of the eye concurrently with the dispensing or at a point in time after the dispensing of the therapeutically desired amount of drug.

This is a division of application Ser. No. 179,129, filed Sept. 9, 1971and now abandoned.

BACKGROUND OF THE INVENTION

This invention relates to a method and device for the controlledcontinuous administration of drug to the eye over a prolonged period oftime. Still more particularly, this invention relates to an ocular drugdevice capable of bioeroding in the environment of the eye concurrentlywith the dispensing or at a point in time after the desired amount ofdrug has been administered.

Presently, diseases of the eye are still conventionally treated byperiodically applying ophthalmic drugs in liquid or ointment form. Whilethis method of administration is suitable in certain instances, aserious shortcoming is the failure of these types of dosage formulationsto dispense the drug in a continuous manner. Periodic application ofthese dosage forms, even though they be applied at intervals during theday and night, results in the eye receiving a massive, butunpredictable, amount of drug at each time of application. The result ofthis intermittent administration is that the level of drug surges to apeak at the time the drug is applied to the eye, followed by a declinein concentration. Thus, a plot of drug in the eye and surroundingtissues vs time, after administration of several dosage forms a day hasthe appearance of a series of peaks which may surpass the toxicthreshold of the drug and valleys which fall below the critical pointneeded to achieve the desired therapeutic effect. Further, drugadministered via an ointment or liquid form of therapy is washed awayrapidly by tear fluid, leaving the eye without medication until the nextapplication. Moreover, in some ocular conditions characterized byconstant deterioration, i.e. glaucoma, continuous treatment offersextremely important therapeutic advantages. Most ointment dosage formspresently available are in unsterilized form, and are generallydifficult to use without impairment of vision.

It was proposed, late last century, to use water soluble drug containinggels of glycerinated gelatin that are shaped to the form of a lamella oreye disk. Such lamellae are applied to the eye to supply drug thereto.In use, the glycerinated gelatin vehicle dissolves almost instantly intear liquid, producing the same type of effect as do liquid dosageforms. Thus, these disks are not suitable for providing for prolonged orsustained continuous release of a drug because of their rapid rate ofdissolution. Further information on these water soluble dosage forms canbe found in Remington's Pharmaceutical Sciences, XIII, pp. 547-8 (MackPublishing Co., Easton, Pa., 1965); Fishburn, An Introduction toPharmaceutical Formulation, p. 116 (Pergman Press Ltd., New York City,N.Y., 1965); and U.S. Pat. No. 273,410, Mar. 6, 1883.

Recognizing these disadvantages, a significant advance has recently beenmade in the field of ophthalmic drug delivery systems. In this regard,U.S. Pat. No. 3,416,530, granted Dec. 17, 1968, entitled "EyeballMedication Dispensing Tablet", and Ser. No. 831,761, filed June 9, 1969,entitled "Ocular Insert", disclose a drug dispensing ocular insert whichslowly releases drug to the eye for prolonged periods of time. Suchocular inserts are fabricated of materials that are biologically inert,non-allergenic, and insoluble in tear liquid. To initiate thetherapeutic program, the ocular insert is placed in the upper or lowersac of the eye bounded by the surfaces of the sclera of the eyeball andconjunctiva of the lid. Since the material from which the ocular insertis formed is insoluble in tear liquid, it retains its integrity andremains intact during the course of therapy, acting as a reservoir tocontinuously release drug to the eye and surrounding tissues at acontrolled rate. On termination of the therapeutic program the ocularinsert is removed from the eye. Thus, a single such ocular insertprovides the complete ophthalmic dosage regimen for a particular timeperiod, on the order of 24 hours or longer. More frequent repeatedapplications which are necessary with liquids, ointments, or watersoluble lamellae are avoided.

While the drug dispensing ocular inserts described above, which deliverdrug to the eye continuously and in a controlled manner over a prolongedperiod of time, have proved to be markedly superior to the prior artointments and liquids, there remain, however, improvements to be made.The ocular insert, after insertion in the eye sac, is designed to remainintact during the course of therapy, and does so since it is formed ofmaterial insoluble in tear liquid. On termination of the therapy programthe insert must be removed, which may present difficulty and discomfortto some patients. In rare instances, the simple removal if made moredifficult by unwanted migration of the insert to the upper fornix, whereit may remain long after the entire drug supply has been released to theeye. Further, as is often conventional in ophthalmic practice,physician-patient contact is not of a sufficient degree so as to insurethat medical instructions from the doctor are accurately carried out bythe patient. Thus, in the case of the use of an insoluble ocular insert,there is no certainty that the patient will remove the device whenscheduled to do so. This is particularly true with elderly patients whooften forget or are simply unable to remove the device due to failingmemory or eyesight.

SUMMARY OF THE INVENTION

Accordingly, it is an object of this invention to provide an improveddrug dispensing ocular insert for the controlled continuousadministration of drugs to the eye over a prolonged period of time.

Still another object of this invention is to provide an improved drugdispensing ocular insert which does not have to be removed from the eyeafter termination of the therapeutic program.

A further object of this invention is to provide an improved method fortreating diseases of the eye.

Another object of this invention is to provide an improved drugdispensing ocular insert for delivering drugs to the eye with increasedefficacy.

A still further object of this invention is to provide a bioerodibleocular device which can be adapted to medications having eitherrelatively high or relatively low solubilities in eye fluids.

In accomplishing these objects, a major aspect of this invention residesin an ocular insert for the controlled continuous administration of apredetermined dosage of drug to the eye, comprising one or morereservoirs, each of the reservoirs comprised of a drug formulationconfined within a bioerodible drug release rate controlling material,the insert being of an initial shape which is adapted for insertion andretention in the sac of the eye bounded by the surfaces of the bulbarconjunctiva of the sclera of the eyeball and the palpebral conjunctivaof the lid, the material continuously metering the flow of atherapeutically effective amount of drug from the reservoir to the eyeat a controlled rate over a prolonged period of time, and wherein theinsert bioerodes in the environment of the eye concurrently with thedispensing or at a point in time after the dispensing of thetherapeutically desired amount of drug.

One embodiment of the invention described above resides in an ocularinsert for the controlled continuous administration of a predetermineddosage of drug to the eye over a prolonged period of time, comrising abody of bioerodible drug release rate controlling material containing adrug formulation confined therein, the body being of an initial shapewhich is adapted for insertion and retention in the sac of the eyebounded by the surfaces of the bulbar conjunctiva of the sclera of theeyeball and the palpebral conjunctiva of the lid, the body continuouslymetering the flow of a therapeutically effective amount of drug to theeye at a controlled rate over a prolonged period of time, and whereinthe body bioerodes in the environment of the eye concurrently with thedispensing or at a point in time after the dispensing of thetherapeutically desired amount of drug.

In another aspect, this invention resides in an ocular insert for thecontrolled continuous administration of a predetermined dosage of drugto the eye, comprising (1) an inner reservoir containing a drugformulation confined therein, and (2) an outer membrane formed from drugrelease rate controlling bioerodible material surrounding the innerreservoir, the membrane being permeable to passage of drug, but at alower rate than through the inner reservoir, the insert being of aninitial shape which is adapted for insertion and retention in the sac ofthe eye bounded by the surfaces of the bulbar conjunctiva of the scleraof the eyeball and the palpebral conjunctiva of the lid, the outermembrane material continuously metering the flow of a therapeuticallyeffective amount of drug from the reservoir to the eye at a controlledrate over a prolonged period of time, and wherein the insert bioerodesin the environment of the eye concurrently with the dispensing or at apoint in time after the dispensing of the therapeutically desired amountof drug.

In still another aspect, this invention resides in an ocular insert forthe controlled continuous administration of a predetermined dosage ofdrug to the eye over a prolonged period of time, comprising a pluralityof reservoirs, each of the reservoirs comprised of a drug formulationconfined within a drug release rate controlling material, the reservoirscharacterized by being either:

1. a microcapsule of an initial size and configuration such as to becapable of being eliminated from the ocular cavity through the punctumwith tear fluid, or

2. a microcapsule of bioerodible material; the reservoirs beingdistributed throughout a bioerodible matrix material permeable to thepassage of drug at a higher rate than through the drug release ratecontrolling material, the latter material metering a therapeuticallyeffective amount of drug from the reservoir to the eye at a controlledrate over a prolonged period of time, the insert being of an initialshape which is adapted for insertion and retention in the sac of the eyebounded by the surfaces of the bulbar conjunctiva of the sclera of theeyeball and the palpebral conjunctiva of the lid, and wherein thereservoir and matrix are eliminated from the ocular cavity by bioerodingin the environment of the eye or the reservoir eliminated by passagethrough the punctum, the elimination taking place concurrently with thedispensing or at a point in time after the dispensing of thetherapeutically desired amount of drug.

Other objects, features and advantages of the invention will become moreapparent from the following description when taken in conjunction withthe drawings and from the claims.

BRIEF DESCRIPTION OF THE DRAWINGS

In the drawings:

FIG. 1 is a view partly in front elevation and partly diagrammatic of ahuman eye, illustrating an ocular insert of this invention is anoperative position soon after insertion in the eye.

FIG. 2 is a view partly in vertical section and partly diagrammatic ofan eyeball and the upper and lower eyelids associated therewith showingthe ocular insert of this invention in operative position.

FIGS. 3, 4, 5, 6 and 7 are cross-sectional views of several embodimentsof ocular inserts of this invention.

DETAILED DESCRIPTION OF THE INVENTION

The term "bioerodible", as used in the specification and claims, isdefined as the property or characteristic of a body of a microporous,solid or gel material to innocuously disintegrate or break down as aunit structure or entity, over a prolonged period of time, in responseto the environment in the eye by one or more physical or chemicaldegradative processes, for example by enzymatic action, oxidation orreduction, hydrolysis (proteolysis), displacement, e.g. ion exchange, ordissolution by solubilization, emulsion or micelle formation, and whichmaterial is thereafter absorbed by the eye and surrounding tissues, orotherwise dissipated, such as by elimination from the ocular cavitythrough the punctum with tear fluid.

As used in the instant specification and appended claim, the term"prolonged period of time" is meant to include time intervals of from atleast 8 hours to approximately 30 days or higher and preferably periodsof from 1 to 8 days. It should be noted that this term is applied withreference to the time interval over which the drug is released and alsowith reference to the time interval over which the insert and componentmaterials bioerode in the environment in the eye, although each of theaforesaid time periods may not necessarily be concurrently coextensivein duration.

The term "reservoir", as used herein to define the drug-containingportion of the ocular insert, is intended to connote a broad class ofstructures capable of fulfilling the intended function and, as will behereinafter more completely developed, includes a plurality of discrete,drug-containing microcapsules or a porous, hollow, solid, gel or liquiddrug-containing body of material. The microcapsule can be formed as ahollow container having the drug therein or be formed as a solid orporous particle having the drug distributed therethrough.

In accordance with the present invention, there is provided an ocularinsert for the controlled continuous dispensing of a predetermineddosage of drug to the eye over a prolonged period of time, comprisingone or more reservoirs, each of the reservoirs comprised of a drugformulation confined within a bioerodible drug release rate controllingmaterial, the insert being of an initial shape which is adapted forinsertion and retention in the sac of the eye bounded by the surfaces ofthe bulbar conjunctiva of the sclera of the eyeball and the palpebralconjunctiva of the lid, the material continuously metering the flow of atherapeutically effective amount of drug from the reservoir to the eyeat a controlled rate over a prolonged period of time, and wherein theinsert bioerodes in the environment of the eye concurrently with thedispensing or at a point in time after the dispensing of thetherapeutically desired amount of drug.

Referring particularly to FIGS. 1 and 2, a human eye is shown, more orless diagrammatically, as comprising an eyeball 1 and upper and lowereyelids 2 and 3, respectively, the eyeball 1 being covered for thegreater parts of its area by the sclera 4 and at its central portion bythe cornea 5. The eyelids 2 and 3 are lined with an epithelial membraneor palpebral conjunctiva. The sclera 4 is also lined with an epithelialmembrane or bulbar conjunctiva which covers the exposed portion of theeyeball including the cornea 5, that portion covering the cornea beingtransparent; that portion of the palpebral conjunctiva which lines theupper eyelids 2 and the underlying portion of the bulbar conjunctivadefining the upper sac 7 and that portion of the palpebral conjunctivawhich lines the lower eyelid 3 and the underlying portion of the bulbarconjunctiva defining the lower sac 11. Upper and lower eyelashes areindicated at 8 and 9, respectively.

An ocular insert 12 is shown in operative position in the lower sac 11of the eye. Other details of the eyeball 1 are not directly concernedwith the structure of the instant invention and, therefore, detailsshowing the description thereof are being omitted in the interest ofbrevity.

To use the ocular insert of the invention, as illustrated in FIGS. 3, 4,5 and 6, it is inserted within the upper 7 or lower sac 11. Placement inthe lower sac is preferred due to the tendency of the eye to rollupwardly during sleeping, known as Bell's phenomenon, which may causediscomfort to some patients if the insert is located in the upper sac 7.The ocular device illustrated in FIG. 7 is inserted in the areasurrounding the corneal surface of the eye lying in both the upper andlower sacs 7 and 11.

Once in place, the ocular insert functions to continuously administer ametered amount of drug from the reservoir to the eye and surroundingtissues over a prolonged period of time through the primary drugtransfer mechanisms of: (1) "Permeation Control Release", i.e. thecontrolled release of the drug by the processes of: (a) diffusivetransfer by controlled flow of drug through the rate controllingmaterial of the insert, and/or (2) "Erosion Control Release", i.e. themetered release of entrapped drug contained in the release ratecontrolling material as the material bioerodes in a controlled andpredetermined manner over a prolonged period of time in response to theaction of the environment in the eye. It will be understood with regardto mechanism (1) above, i.e. Permeation Control Release, that the ratecontrolling material can be either of an imperforate or microporousnature, and therefore flow of drug can be effected by moleculardiffusion as is the mode in the case of imperforate rate controllingmaterials, or by viscous diffusive flow as is the mode in the case ofmicroporous rate controlling materials which are impregnated with eyefluids. Both of these modes of drug transfer are intended to be includedherein. It is further intended to include as microporous materialhydrophilic materials which may be initially imperforate, but whichswell and become microporous in structure in the environment of the eye.In any event, after the drug leaves the ocular insert, it is transportedto the eye and surrounding tissues, including the corneal epithalium, bythe flow of tear liquid and the blinking action of the eyelids.

Any material having the ability to control the rate of release of drugover a prolonged period of time by either of these mechanisms, or acombination of these mechanisms, (1) or (2) above, is herein defined as"drug release rate controlling material".

Another mechanism for drug release which must be considered in the caseof inserts made from water permeable materials and water soluble drugsis that of simple dissolution of the drug, as for example by leaching.Release of drug by this mode is not preferred due to the fact that it isdifficult to control.

Depending upon the particular embodiment, the drug reservoir can be ofdrug release rate controlling material or otherwise. However, as isapparent in the latter case, the drug must first pass through drugrelease rate controlling material prior to reaching the eye. It istherefore critical to the practice of this invention for all embodimentsthat the drug pass through the drug release rate controlling material tometer the flow thereof at some point after or concurrent with therelease of drug from the reservoir and prior to reaching the eye. Thedrug release rate controlling material can be of the barrier or membranetype for example as shown in FIGS. 3 or 4, or of the matrix type forexample as shown in FIG. 5.

It has been found that the ocular insert of this invention providesseveral important advantages over known devices and methods ofadministering drugs to the eye. One important advantage of the claimedinsert resides in the fact that, in addition to the ability toeffectively control the amount of drug dispensed in a continuous mannerand over a prolonged time span with the attendant advantages thereto, itis not necessary for the patient to remove the device from the eye atthe termination of the therapeutic program as a result of itsbioerodible characteristics. Thus, the devices of this invention lendthemselves to the obtainment of the benefits of continuousadministration and also minimize the disadvantages of having to removethe ocular insert from the eye. This latter aspect is a particularlyimportant feature since, by the very nature of the anatomy involved,tasks such as removal of an object from the eye are made increasinglymore difficult. Moreover, risks of patient non-compliance with medicalinstructions, a well known factor in ophthalmic practice, are minimizedto a large degree by the inherent drug administration pre-program dosageand terminating capabilities of the devices of this invention.

Yet, another important advantage of the devices of this inventionresides in the ability to effectively control the rate of release ofdrug in a zero order manner, that is, the rate of release of drug issubstantially independent of time throughout the major portion of theadministration period. This aspect further enhances the therapeuticbenefits to be obtained by insuring that the drug is both continuouslyavailable and at substantially the same dosage rate. Alternatively, drugcan be administered from the device according to other predeterminedtime release patterns. One embodiment that is particularly suited toprovide drug release patterns that are for example sinusoidal,parabolic, and the like, is that illustrated in FIG. 6. As more fullydescribed hereinafter, varying release patterns can be obtained byappropriate selection of reservoirs having different drug release ratecharacteristics for use in a given ocular insert.

Still another benefit to be derived by use of the instantly claimedinsert is the increased therapeutic efficacy per unit amount of drugadministered.

The ocular insert can be fabricated in any convenient shape forcomfortable retention in the sac of the eye. Thus, the marginal outlineof the ocular insert can be ellipsoid, donut-shape, bean-shape,banana-shape, circular, rectangular, etc. In cross-section, it can bedoubly convex, concavo-convex, rectangular, etc. as the ocular insert inuse will tend to conform to the configuration of the eye, the originalcross-sectional shape of the device is not of controlling importance.Dimensions of the device can vary widely. The lower limit on the size ofthe device is governed by the amount of the particular drug to besupplied to the eye and surrounding tissues to elicit the desiredpharmacologic response, as well as by the smallest sized device whichconveniently can be inserted in the eye. The upper limit on the size ofthe device is governed by the geometric space limitations in the eye,consistent with comfortable retention of the ocular insert. Satisfactoryresults can be obtained with an ocular device for insertion in the sacof the eye of from 4 to 20 millimeters in length, 1 to 12 millimeters inwidth, and 0.1 to 2 millimeters in thickness. Several embodiments ofthese inserts are exemplified in FIGS. 3 through 7, inclusive.

In one aspect of this invention, as illustrated in FIGS. 3 and 4, theocular insert comprises (1) an inner reservoir containing a drugformulation confined therein, and (2) an outer membrane formed from drugrelease rate controlling bioerodible material surrounding the innerreservoir, the membrane being permeable to passage of drug, but at alower rate than through the inner reservoir, the insert being of aninitial shape which is adapted for insertion and retention in the sac ofthe eye bounded by the surfaces of the bulbar conjunctiva of the scleraof the eyeball and the palpebral conjunctiva of the lid, the outermembrane material continuously metering the flow of a therapeuticallyeffective amount of drug from the reservoir to the eye at a controlledrate over a prolonged period of time, and wherein the insert bioerodesin the environment of the eye concurrently with the dispensing or at apoint in time after the dispensing of the therapeutically desired amountof drug.

FIG. 3 illustrates generally, by reference numeral 19, an embodiment ofthis invention wherein the bioerodible ocular insert is comprised of aninner reservoir 20 which is formed of a bioerodible matrix materialhaving drug 21 dispersed therethrough. Surrounding matrix 20 is a ratecontrolling membrane 22 which is also bioerodible in the eye. Bothmatrix 20 and membrane 22 are permeable to the passage of drug bydiffusion, that is, molecules of the drug can dissolve in and diffusethrough these materials; however, the permeability of membrane 22 todrug is lower than from the matrix 20 so that release of drug throughmembrane 22 is the drug rate release controlling step from the ocularinsert. The inner matrix 20 serves as a depot or reservoir source forthe drug and can be a porous, solid or gel material. Drug molecules movethrough the inner matrix 20 by diffusion, thereby uniformly saturatingthe innermost surface of membrane 22 with drug after equilibriumconditions are reached. Drug is continuously metered through and removedfrom the outer surface of membrane 22 where it is made available to theeye fluids and tissues.

An advantage of the insert of the type illustrated in FIG. 3 is that itcan be adapted to release drug in a zero order manner, that is, at aconstant rate and over a prolonged period of time. By the appropriatedesign and selection of materials, drug release from the device ispreferably primarily effected by a "permeation control releasemechanism" and includes a sequence of steps characterized by controlleddrug diffusion through membrane 22 followed by a combination of leachingof drug by the tear liquid and the blinking action of the eyelids inorder to transport the drug from the outermost surface of membrane 22 tothe eye and surrounding tissues. Release rate is controlled by systemvariables such as the diffusivity and solubility of the drug in themembrane material 22 and the thickness of this material. Design of anocular device, therefore, necessitates selection of materials and otherparameters in order to provide the proper release rates and dosageregimen, depending upon the particular drug to be used. The followingare generalized considerations in order to properly design an ocularinsert of the type illustrated in FIG. 3.

The mechanism by which diffusion is achieved may be explained on thebasis of an activity or chemical potential gradient wherein the confineddrug relieves its internal concentration by spreading out into theadjacent medium. As the drug is removed from the device and absorbed byeye tissues or carried away by the eye fluids, the diffusive actioncontinues until the source of drug 21 has been substantially consumed.The drug will have a definite and characteristic rate of passage throughthe release rate controlling material of the insert. It is preferred,although not essential, that drug 21 essentially be depleted or consumedfrom the reservoir 20 before membrane material 22 completely bioerodes.However, if it is desired to obtain a zero order drug release rate overthe active releasing period of the insert, prior depletion of drug is anessential requirement. Of course, it will be appreciated that the deviceof type shown in FIG. 3 makes possible drug-time patterns of releaseother than zero order. Another reason for the depletion of drug frommatrix reservoir 20 prior to the complete erosion of membrane material22 is to eliminate the possibility of the sudden release of drug fromthe reservoir to the eye at the time of total erosion of membrane 22, asa result of the high permeability of material 20 to drug, as hereinafterdescribed. Therefore, membrane material 22 should be selected withregard to its erosion rate, thickness and permeability to drug 21 inrespect to the amount of drug in core material 20. It will, of course,be appreciated that the inner core material 20 will not begin to erodeuntil free to contact eye fluids, which time will be subsequent to thesubstantially complete erosion of outer membrane 22.

The reservoir 20 primarily functions as a depot for the drug rather thanas a rate control barrier. Therefore, it should be highly permeable topassage of drug by diffusion. In contrast, membrane 22 which acts as therate-limiting barrier to control drug release must be only slowlypermeable to the passage of drug, with the exact value determined by thedesired release rate. Thus, it is important to the successful practiceof this invention that the membrane 22 have a lower permeability to thedrug by diffusion than does the matrix material 20. The initial ratio ofpermeability rates for drug for the matrix material 20 to membranematerial 22 should be approximately between 10:1 and 100:1, andpreferably between 2:1 and 10:1. It will be noted that the effectivedrug release rate through the membrane 22 may tend to increase somewhatin the case wherein membrane erodes from its surface, and the effectiverelease rate through the membrane material 22 will tend to decreasesomewhat as the concentration of drug in the reservoir 20 depletes.These opposite effects tend to compensate each other to a large degreeso as to give an overall uniform rate throughout most of the drugrelease period. However, in cases where the release rate of the deviceis not overly sensitive to changes in thickness in the membranematerial, or where the change in thickness of the membrane material aresmall during the drug releasing period, it is preferred, in order toobtain zero order drug release, that the drug be sparingly soluble inthe reservoir matrix material so as to retain substantially the samethermodynamic activity of the drug throughout the release period. By"sparingly soluble" is meant that the fractional amount of drugdissolved in the reservoir material should be in range of from 0.1% to35% by weight of the total amount of drug to be delivered, such thatsolid particles of drug are present throughout most of the drug releaseperiod. Moreover, for best results, the rate of passage of drug throughmembrane 22 should not exceed the rate of removal or clearance of drugfrom the exterior of the membrane by eye tissues. This insures that thedrug delivery rate is controlled by diffusion through the membrane 22,which can be controlled.

As disclosed above, the selection of appropriate materials forfabricating the ocular inserts will be dependent upon their erosionrates in the eye. The erosion rate of outer membrane material 22 in theeye is determined by the desired ophthalmic dosage regimen, as well asthe length of time the device is to remain in the eye. Under optimumconditions, the erosion rate should be such that substantially all ofthe membrane material 22 bioerodes in the eye tissue soon after the drughas been substantially depleted from the reservoir 20, preferably nolater than in a period of from 24 hours thereafter, if possible.

The erosion rate of inner core material 20 can be the same as, greaterthan, or less than the erosion rate of outer membrane material 22,although it is preferred that it be greater. The preference of thehigher erosion rate for the inner matrix material 20 is predicated onthe fact that the primary function of this material is to serve as areservoir for the drug 21. Erosion of this material does not commenceuntil the drug 21 contained therein has been substantially depleted andthe erosion of outer layer 22 essentially completed. At this stage, nopurpose is served by further retention of core material 20 in the eye.It is preferred that the erosion rate for core material 20 is such thatall of the material bioerodes in the eye tissue in a relatively quickperiod of time, preferably within 8 hours after the substantiallycomplete erosion of the outer membrane 22 has taken place.

It will of course be appreciated that correlation of the optimum desiredmaterial erosion rate and the drug release rate for a given membranematerial 22 may in some cases be difficult under certain designconditions. In these cases, selection of a material having the desiredoptimum drug release rate should be made with the proviso that theerosion rate be slow enough to ensure that the membrane layer 22 doesnot totally erode prior to the depletion of drug from core material 20.If this procedure is followed, there will be a period of time in whichthe ocular insert remains in the eye but dispenses no drug. This,however, is not of serious consequence, as a fresh ocular device can beinserted concurrent with the final stages of the erosion of the originaldrug depleted device.

The thickness of the inner core 20 can vary, consistent with dimensionsresulting in comfortable retention of the device in the eye and physicalcapability to incorporate the desired amount of drug. The thickness ofouter membrane 22 can also vary, depending upon overall comfortableretention of the device in the eye, as well as providing the desireddrug release rates and a sufficient mass of material so as to enable thesubstantially complete depletion of drug from core 20 prior to thecomplete erosion of the layer 22, thereby insuring, if desired, thatdrug 21 is advantageously released from the insert in a zero ordermanner as heretofore discussed.

In general, to design a device of the type shown in FIG. 3 it is firstnecessary to select the drug to be used, its dosage, and the period oftherapy. This establishes the required drug release rate and amount ofdrug to be incorporated in the device. Materials for both the reservoirand rate controlling membrane which have the appropriate permeabilitycharacteristic and erosion rates can then be correlated with thicknessand effective surface release area to fabricate a device which metersthe desired amount of drug to the eye over the established period oftime and thereafter completely erodes in the eye.

FIG. 4 illustrates generally, by reference numeral 30, anotherbioerodible ocular insert of this invention having a hollow interiorreservoir 32 containing drug formulation 21 in the reservoir 32. Ratecontrolling bioerodible membrane 22 surrounds the reservoir 32 andcontrols the flow of drug from the reservoir 32 to the eye. Thisembodiment differs from that illustrated in FIG. 3, mainly in thattherein the reservoir 20 is formed of a matrix material with the drugdispersed therethrough, whereas in the embodiment of FIG. 4 the drug 21is confined in the hollow reservoir container 32. Alternatively (notshown), the drug contained within the hollow reservoir 32 can besurrounded with an additional layer of material to facilitate thehandling of drug during fabrication. This material should be highlypermeable to drug in contrast to rate controlling membrane 22. Theinsert shown in FIG. 4 operates in a manner similar to the deviceillustrated in FIG. 3, as described above. It is imperative that thedrug 21 be depleted from the reservoir 32 prior to the complete erosionof rate controlling membrane 22 in order to avoid a sudden and unwantedrelease of drug from the reservoir 32 to the eye.

Another aspect of the invention resides in an ocular insert for thecontrolled continuous administration of a predetermined dosage of drugto the eye over a prolonged period of time, comprising a body ofbioerodible drug release rate controlling material containing a drugformulation confined therein, the body being of an initial shape whichis adapted for insertion and retention in the sac of the eye bounded bythe surfaces of the bulbar conjunctiva of the sclera of the eyeball andthe palpebral conjunctiva of the lid, the body continuously metering theflow of a therapeutically effective amount of drug to the eye at acontrolled rate over a prolonged period of time, and wherein the bodybioerodes in the environment of the eye concurrently with the dispensingor at a point in time after the dispensing of the therapeuticallydesired amount of drug. FIG. 5 illustrates one embodiment of the abovedescribed ocular insert, wherein the device 50 is comprised of a body ofmicroporous, solid or gel bioerodible drug release rate controllingmatrix material 51 having drug 21 dispersed therethrough. The matrixmaterial 51 functions both as a drug reservoir source and rate releasecontrolling material to continuously dispense a metered amount of drugto the eye and surrounding tissues over a prolonged period of timethrough the hereinabove discussed primary drug transfer mechanisms of:

1. Permeation Control Release, and/or

2. Erosion Control Release The actual control mechanism is dependentupon the design of the insert with particular regard to the combinationselection of drug and release rate controlling material. The followingare generalized considerations to be made in order to properly design anocular insert with particular regard to the administration of drugswhich are water soluble.

"Water soluble" is defined to mean materials which are soluble in waterto a degree which exceeds approximately 50 parts per million.

In cases where the drug to be released is not water soluble, or in caseswhere the drug is water soluble and the drug release rate controllingmaterial is substantially water impermeable, (hydrophobic), satisfactorydevices can be made with the actual drug release from the device to theeye being effected by either of the transfer mechanisms, or acombination of the transfer mechanisms, (1) and (2) above. The actualmode of drug transfer will depend upon such factors as whether the drugrelease rate controlling material is of a hydrophobic or hydrophilicnature, whether the drug is soluble or insoluble in the rate controllingmaterial, and on the erosion pattern of the rate controlling material,e.g. surface erosion or otherwise. However, it has been found that it isnot preferred to deliver water soluble drugs using highly waterpermeable release rate controlling matrix materials, e.g. hydrophilicmaterials, over prolonged periods of time because the rate of release ofdrug is governed by that of simple dissolution of the drug in tearfluid. It is therefore preferred in these cases that certainmodifications be made to insolubilize the drug. Insolubilization of thedrug can be accomplished in a number of ways, among which include theforming of pharmaceutically acceptable derivatives of the drug which arenot water soluble. These derivatives can be prepared by art knowntechniques and then used in the practice of the invention. Of course,the drug derivative should be such as to convert to the active drugwithin the body through the action of body enzymes, assistedtransformations, pH, specific organ activities, and the like.Alternatively, insolubilization of the drug can be effected by coatingthe drug, such as by microencapsulating the drug, with a material todecrease the rate of release of drug by simple dissolution in tearfluid. Therefore, devices of the type illustrated in FIG. 5 arepreferrably made, in cases where the drug is water soluble and the ratecontrolling matrix material is water permeable, by insolubilizing thedrug. Methods and materials for microencapsulating the drug in order todecrease the drug solubility in water are described hereinafter withregard to the reservoirs in FIG. 6. These microencapsulating methods,structures and materials are suitable for the drug encapsulation in theembodiment of the type illustrated in FIG. 5, with the qualificationthat in FIG. 5 the microcapsule material does not provide the releaserate controlling step from the device as it does in the deviceillustrated in FIG. 6.

In still another aspect, as illustrated in FIG. 6, this inventionresides in an ocular insert for the controlled continuous administrationof a predetermined dosage of drug to the eye over a prolonged period oftime, comprising a plurality of reservoirs, each of the reservoirscomprised of a drug formulation confined within a drug release ratecontrolling material, the reservoir characterized by being either:

1. a microcapsule of initial size and configuration such as to becapable of being eliminated from the ocular cavity through the punctumwith tear fluid, or

2. a microcapsule of bioerodible material; the reservoirs beingdistributed throughout a bioerodible matrix material permeable to thepassage of drug at a higher rate than through said drug release ratecontrolling material, the latter material metering a therapeuticallyeffective amount of drug from the reservoir to the eye at a controlledrate over a prolonged period of time, the insert being of an initialshape which is adapted for insertion and retention in the sac of the eyebounded by the surfaces of the bulbar conjunctiva of the sclera of theeyeball and the palpebral conjunctiva of the lid, and wherein thereservoir and matrix are eliminated from the ocular cavity by bioerodingin the environment of the eye or the reservoir eliminated by passagethrough the punctum, the elimination taking place concurrently with thedispensing or at a point in time after the dispensing of thetherapeutically desired amount of drug.

FIG. 6 illustrates an ocular insert 60 of this invention, particularlysuited for administering a water soluble drug 64. The drug deliverydevice 60 is comprised of a bioerodible matrix 62 having dispersedtherethrough a plurality of reservoirs 61. The reservoirs 61 aremicrocapsules comprised of a drug whether in solid form, liquid form orin admixture with a carrier, confined within a drug release ratecontrolling material. Drug molecules released from the reservoirs 61pass into the matrix 62 and then migrate through the matrix 62 foradministration of drug to the eye. Release of drug from the reservoir isthe rate controlling step for release of drug from the device. Inconstruction, the device can be viewed as a single unit devicecomprising two structures acting in concert for effective drugadministration to the eye. One structure pertains to the reservoirs 61which are microcapsules comprising a microbody of drug release ratecontrolling material having drug 64 confined therein, and the otherstructure relates to the bioerodible matrix 62 housing the reservoirsand is formed of a material permeable to the passage of drug.

The reservoirs 61 can be formed as a hollow container having a drugtherein formed from drug release rate controlling material.Additionally, the reservoir 61 can be a solid particle having a drugdistributed therethrough and formed of a drug release rate controllingmaterial. Alternatively, the reservoir 61 can be a porous structureformed of a material possessing drug release rate controllingproperties. Reservoir 61 can have the conventional aggregate structureand particulate structure of conventional geometric shape. Bycontrolling the structure of the reservoirs of the drug delivery device,the invention makes possible a drug time pattern of release, including azero order drug release. Thus, in the presently preferred embodimentsfor obtaining a zero order release, the reservoir is formed as a capsulecontaining the drug therein and surrounded by a rate controllingmembrane, or the reservoir is a solid matrix with a limited number ofdiscrete particles of drug contained therein. Other patterns of releasecan be obtained, e.g. sinusoidal, parabolic and the like by theappropriate selection of reservoirs having different release rates whichare then dispersed in a given matrix.

The materials suitable for fabricating the reservoir 61, whether ofhollow, solid, porous, semi-porous or the like structures, are generallythose materials capable of forming membranes with or without pores orvoids, or coatings through which the drug can pass at a controlled rateby the process of diffusion. Suitable materials for forming thereservoirs are naturallyoccurring or synthetic materials that arenon-toxic and which preferrably have a low solubility and/or lowdiffusivity to water. In general, these qualities will be possessed byrate release controlling materials that are hydrophobic in nature. Therate controlling materials used for the reservoir 61 can be bioerodibleand alternatively, when the reservoir 61 is of an initial size andconfiguration such as to be capable of being eliminated from the ocularcavity through the punctum with tear fluid can be made ofnon-bioerodible material. Microcapsules, preferably of approximately 100micron size or less, will be of suitable dimension for proper punctumpassage.

Exemplary non-bioerodible materials suitable for fabricating themicrocapsules when of an initial size such as to pass through thepunctum are drug release rate controlling materials such as hydrophobicpolymers, e.b. polyvinylchloride, nylon, silicone rubber, cholesterol;substituted alkyl celluloses such as hydroxypropyl methyl cellulose,methyl cellulose, ethyl cellulose, cellulose acetate; waxes, e.g.paraffin, ethylene wax, hydrogenated castor oil; C₁₀ to C₂₀ fatty acids,e.g. stearic acid, palmitic acid; hydrophilic polymers, e.g. polymerizedesters of methacrylic acid (Hydron), and the like. Bioerodible materialssuitable for preparing the microcapsule reservoirs are disclosedhereinafter. The actual material selected for fabricating themicrocapsule reservoir is one that can slow down the rate of release ofthe water soluble drug to the desired level. Preferred are thehydrophobic materials. Although hydrophilic type materials can sometimesbe employed for fabricating the reservoir in cases where the watersoluble drug is not too highly permeable therein, in most cases thickercoatings of microcapsule material and larger microcapsule diameters willbe required than for hydrophobic type microcapsule materials, asexplained immediately hereinafter.

Among other factors which must be considered, in addition to the natureof the reservoir rate controlling material, and which affect the rate ofrelease of drug from the microcapsule, are the microcapsule size, thedensity of drug and the thickness of the reservoir wall. Qualitativeguides in this regard are that the rate of release of drug will decreasewith corresponding increasing values for each of these parameters. Atypical combination of drug and coating is a 100 micron chloramphenicolparticle coated with polylactic acid to a thickness of 3 microns withthe microcapsule being dispersed in a cross-linked gelatin matrix.

Additionally, if desired, particles of a known drug carrier, such asstarch, gum acacia, charcoal, gum tragacanth, calcium carbonate,polyvinylchloride, and the like, can be impregnated with the drug andencapsulated with another material such as the encapsulating materialspreviously discussed which function as a membrane to meter the flow ofdrug to the matrix.

Any of the standard encapsulation or impregnation techniques known inthe art can be used to prepare the microcapsules 61 to be incorporatedinto the matrix material 62 in accord with this invention. Thus, thedrug, a mixture of drug, or drug solution can be added to theencapsulating material in liquid form and uniformly distributedtherethrough by mixing; or solid encapsulating material can beimpregnated with the drug by immersion in a bath of the drug to causethe drug to diffuse into the material. Subsequently, the solid materialcan be reduced to fine microcapsules by grinding, each of themicrocapsules comprising drug coated with and distributed throughout theencapsulating material. Alternatively, fine particles or solutions ofthe drug can be encapsulated with a coating. One suitable techniquecomprises suspending dry particles of the drug in an air stream andcontacting that stream with a stream containing the encapsulatingmaterial that coats the drug with a membrane permeable to drug.

Another standard method of microencapsulation suitable for the purposeof the invention is the coacervation technique. The coacervationtechnique of fabrication as conventionally employed consists essentiallyof the formation of three immiscible phases, a liquid manufacturingphase, a core material phase and a coating phase with deposition of theliquid polymer coating on the core material and rigidizing the coating,usually by thermal, cross-linking or desolvation techniques to formmicrocapsules. Techniques for preparing microcapsules, such as theclassic Bungenberg de Jong and Kaas method are reported in Biochem. Z,Vol. 232, pp. 338-345, 1931; Colloid Science, Vol. 11, "ReversibleSystem", edited by H. R. Kruyt, 1949, Elsevier Publishing Company, Inc.,New York; J. Pharm. Sci., Vol. 59, No. 10, (1970), pp. 1367-1376; and,Remington's Pharmaceutical Science, Vo. XIV, Mack Publishing Company,Easton, Pa., 1970, pp. 1676-1677. Other procedures for preparingmicro-capsules are set forth in West German Patent No. DT-1939-066; andthe like.

Materials suitable for use as the matrix material 62 in the device ofthe type illustrated in FIG. 6 must be bioerodible and permeable topassage of drug at a rate which is greater than the permeation of drugthrough the reservoir material. Therefore, it is not necessary for thematrix material 62 to have drug release rate controlling properties. Thebioerosion rate of matrix material 62 can be such that the materialbioerodes concurrently with the dispensing of the drug from thereservoir 61 or at a point in time after the dispensing of the desiredamount of drug from the reservoir. It is preferred, however, althoughnot critical to the successful practice of the invention, that thebioerosion pattern and rate of the matrix material be such that the drugbe substantially depleted from the reservoir 61 prior to the release ofthe reservoir from entrapment within the matrix material 62 andelimination by bioerosion or by passage through the punctum. This ispredicated on the fact that the primary function of the matrix materialis to serve as a carrier or housing for the reservoir 61. The matrixmaterial can be of a water permeable or water impermeable naturealthough when the drug is water soluble, the impermeable materials arepreferred.

Although the device of the type illustrated in FIG. 6 is particularlywell suited to the administration of water soluble and so describedabove, it will be appreciated that it is equally well adapted to theadministration of drugs as hereinafter set forth which are not watersoluble and with each or both the reservoir and matrix also being formedfrom substantially water permeable or water impermeable materials.

Devices of the type shown in FIGS. 5 and 6 can be designed by firstselecting the drug to be used, its dosage, and the period of therapy.This establishes the required drug release rate and amount of drug to beincorporated in the device. Materials having the appropriate drugrelease rate characteristics and erosion rates can then be correlatedwith the effective surface release area to fabricate a device whichmeters the desired rate of the drug to the eye over the establishedperiod of time. A particular added advantage of a device of the type asillustrated in FIG. 6 is the fact that the number of reservoirs employedcan be varied in order to achieve the desired drug release rate from thedevice.

FIG. 7 illustrates a donut-shaped outline of an ocular insert 70 of thisinvention. The insert is comprised of a hollow center portion 72 whichfits over the corneal portion 5 of the eye with the body of bioerodibledrug rate release controlling matrix material 71 resting on the scleralsurface 4 and having drug 21 dispersed therein. The hollow centralportion 72 should be of a size such that the matrix material 71 does nottouch the corneal area of the eye which is sensitive to pain andobstructs the vision of the patient. In order to facilitate insertion ofthe ocular device in the eye, the matrix material 71 can beconcentrically affixed to the outer extremity of a contact lens by meansof any of the well known dermatologically acceptable pressure-sensitiveadhesives, such as the esters of acrylic and methacrylic acid with loweralkyl alcohols, e.g. n-butanol, 2-methyl pentanol, and the like.Insertion of the device in the eye can then be made by using any of thewell known tools commonly employed to insert contact lenses. Inoperation, this device functions in a manner similar to that describedin FIG. 5.

Any of the drugs used to treat the eye and surrounding tissues can beincorporated in the ocular insert of this invention. Also, it ispractical to use the eye and surrounding tissues as a point of entry forsystemic drugs or antigens that ultimately enter circulation in theblood stream, or enter the naso-pharyngeal area by normal routes, andproduce a pharmacologic response at a site remote from the point ofapplication of the ocular insert. Thus, drugs or antigens which willpass through the eye or the tissue surrounding the eye to the bloodstream or to the nasal-pharyngeal, esophageal or gastrointestinal areas,but which are not used in therapy of the eye itself, can be incorporatedin the ocular insert.

Suitable drugs for use in therapy of the eye with the ocular insert ofthis invention consistent with their known dosages and uses are withoutlimitation: antibiotics such as tetracycline, chlortetracycline,bacitracin, neomycin, polymyxin, gramicidin, oxytetracycline,chloramphenicol, gentamycin, and erythromycin; antibacterials such assulfonamides, sulfacetamide, sulfamethizole and sulfisoxazole,antivirals, including idoxuridine; and other antibacterial agents suchas nitrofurazone and sodium propionate; antiallergenics such asantazoline, methapyriline, chlorpheniramine, pyrilamine andprophenpyridamine; anti-inflammatories such as hydrocortisone,hydrocortisone acetate, dexamethasone, dexamethasone 21-phosphate,fluocinolone, medrysone, prednisolone, methylprednisolone, prednisolone21-phosphate, prednisolone acetate, fluoromethalone, betamethasone andtriamcinolone; decongestants such as phenylephrine, naphazoline, andtetrahydroazoline; miotics and anticholinesterases such as pilocarpine,eserine salicylate, carbachol, di-isopropyl fluorophosphate, phospholineiodide, and demecarium bromide; mydriatics such as atropine sulfate,cyclopentolate, homatropine, scopolamine, tropicamide, eucatropine, andhydroxyamphetamine; and sympathomimetics such as epinephrine.

Drugs can be in various forms, such as unchanged molecules, componentsof molecular complexes, or nonirritating, pharmacologically acceptablesalts such as hydrochloride, hydrobromide, sulfate, phosphate, nitrate,borate, acetate, maleate, tartrate, salicylate, etc. For acidic drugs,salts of metals, amines, or organic cations (e.g. quaternary ammonium)can be employed. Furthermore, simple derivatives of the drugs such asethers, esters, amides, etc. which have desirable retention, release orsolubility characteristics, but which are easily hydrolized by body pH,enzymes, etc., can be employed. The amount of drug incorporated in theocular insert varies widely depending on the particular drug, thedesired therapeutic effect, and the time span for which the ocularinsert will be used.

The above drugs and other drugs can be present in the reservoir alone orin combination form with pharmaceutical carriers. The pharmaceuticalcarriers acceptable for the purpose of this invention are the art-knowncarriers that do not adversely affect the drug, the host, or thematerial comprising the drug delivery device. Suitable pharmaceuticalcarriers include sterile water; saline; dextrose; dextrose in water orsaline; condensation products of castor oil and ethylene oxide combiningabout 30 to about 35 moles of ethylene oxide per mole of castor oil;liquid glyceryl triester of a lower molecular weight fatty acid; loweralkanols; oils such as corn oil; peanut oil; sesame oil, and the like,with emulsifiers such as mono- or di-glyceride of a fatty acid, or aphosphatide, e.g. lecithin, and the like; glycols; polyalkylene glycols;aqueous media in the presence of a suspending agent, for example, sodiumcarboxymethylcellulose; sodium alginate; poly(vinylpyrrolidone); and thelike, alone, or with suitable dispensing agents such as lecithin;polyoxyethylene stearate; and the like. The carrier may also containadjuvants such as preserving, stabilizing, wetting, emulsifying agents,and the like.

To provide compatibility with the eye and surrounding tissues, at leastfor the initial period after insertion, the surface of the ocular insertin contact with the eye can be coated with a thin layer, e.g. from 1 to2 microns thick, bioerodible hydrophilic material. Exemplary of thesuitable materials for this purpose are the water soluble hydrophilicpolymers of uncross-linked hydroxyalkyl acrylates and methacrylates, asdisclosed in U.S. Pat. No. 3,576,760, e.g. Hydron-S, gelatin,polysaccharides, e.g. agar, gum arabic, and the like.

The ocular insert is intended to provide a complete dosage regimen foreye therapy over this prolonged period. Therefore, the amount of drug tobe incorporated in the device is determined by the fact that sufficientamounts of drug must be present to maintain the desired dosage levelover the therapeutic treatment period. Typically, from 1 microgram to 1gram or larger of drug is incorporated in the ocular insert, the exactamount of course depending upon the drug used and treatment period.Illustratively, in order to treat glaucoma in an adult human, the dailyrelease dosage should be in the range of between 25 micrograms to 1000micrograms of pilocarpine per day. Thus, for example, using pilocarpinewith a device intended to remain in place for 7 days, and with a releaserate of 500 micrograms of drug per day, 3.5 milligrams of pilocarpinewill be incorporated in the device. Other devices containing differentamounts of drug for use for different time periods and releasing drug athigher or lower controlled rates are also readily made by the invention.

Further, in practicing this invention one can employ any of theaforementioned listed drugs, consistent with their known dosages anduses, to establish a release rate, e.g. micrograms/insert/day. Exemplaryof the dosages to be used are:

    ______________________________________                                        Antibiotics, such as                                                           polymixin:      250 micrograms/insert/day                                    Sulfonamides, such as                                                          sulfacetamide:  500 micrograms/insert/day                                    Antivirals, such as                                                            idoxuridine:     5 micrograms/insert/day                                     Anti-inflammatories,                                                           such as hydrocortisone                                                        acetate or prednisolone:                                                                      500 micrograms/insert/day                                    ______________________________________                                    

Materials which are generally suitable for use as the bioerodible drugrelease rate controlling microcapsules, membrane and matrix materials ofthe ocular inserts of this invention and for the bioerodible innerreservoir 20 in FIG. 3 and matrix 62 in FIG. 6 are those materials whichare non-toxic and compatible with the drug used, with the particularselection being made consistent with eariler comments made regardingdesired erosion and release rates. Exemplary of the materials which canbe employed for these structures are:

1. -Polyanhydrides

Hydrolytically biodegradable polyanhydride polymers of the generalformula: ##STR1## which are the reaction products obtained bypolymerization of aliphatic or aromatic monomeric dibasi acids of theformula:

    HOOC-R-COOH                                                II

or the anhydrides or mixtures of these acids wherein:

R is a radical of the formula --T-- or --Y--;

Y is a radical containing mono or dinuclear arylene group such asphenylene; substituted phenylene, e.g. hydroxy phenylene, C₁ --C₇ alkylphenylene, C₁ --C₇ alkoxy phenylene, bis-(phenoxy) C₁ -C₇ alkylenes; andthe like;

X has a value such that the molecular weight of the polymer ispreferably not greater than 50,000, although higher values can beemployed;

T is an aliphatic alkylene or alkylene ether radical containing from 2to 14 carbons and preferably from 4 to 10 carbons in the backbone chain,optionally with a minor amount of branching, such as methylene,ethylene, propylene, hexylene, 2methyl-propylene, 4 ethyltetradecylene,and the like.

Among the representative monomers can be included adipic acid, pimelicacid, suberic acid, azelaic acid, sebacic acid, succinic acid, glutaricacid, trimesic acid, etc.

These polyanhydrides (1) are known materials and can be convenientlyprepared by condensing the corresponding dibasic acid or anhydride inthe presence of SOCl₂, benzene and a lower alkyl ester of acetic acidsuch as ethyl acetate. Alternatively, the desired dibasic acid oranhydride thereof can be mixed with acetic anhydride to form a mixedanhydride which, on further heating, yields the desired polymericanhydride. Further description of methods for the preparation of thesematerials can be found in U.S. Pats. No. 2,073,799, 2,668,162,2,676,945; and Introduction to Polymer Chemistry, Stille, WileyPublishing Co. (1962). The polyanhydride polymers (1) per se, theirpreparation as exemplified, and use form no part of the presentinvention.

2. - Polyesters

Polyesters of the general formula: ##STR2## and mixtures thereof,wherein: W is a radical of the formula --CH₂ --; or ##STR3## y has avalue such that the molecular weight of the polymer is from about 4,000to 100,000.

These polymers are polymerization condensation products of monobasichydroxy acids of the formula:

    C.sub.n H.sub.2n (OH)COOH                                  IV

wherein n has a value of 1 or 2 especially lactic acid and glycolicacid. Also included are copolymers derived from mixtures of these acids.The preparation of polymers of the formula III per se, forms no part ofthe present invention and several procedures are available and reportedby Filachione, et al, Industrial and Engineering Chemistry, Vol. 36, No.3, pp. 223-228, (March 1944; Tsuruta, et al. Macromol. Chem., Vol. 75,pp. 211-214 (1964), and in Unites States Pat. Nos. 2,703,316; 2,668,162;3,297,033; and 2,676,945.

3. - Cross-Linked Anionic Polyelectrolytes

Membrane and matrix structures comprising crosslinked substantiallywater insoluble polymeric coordination complexes. These products can bemade by several alternative procedures.

Method A comprises the sequential steps of:

a. preparing an aqueous solution containing an initially water solubleanionic polyelectrolyte, and adding thereto a polyvalent metal cationcapable of coreacting therewith to form a water insoluble cross-linkedprecipitate;

b. adding to said mixture a sufficient amount of complexing reagent inthe form of an electron donor molecule to render the reaction productwater soluble by forming a coordination complex with the reactants;

c. fabricating the solution into the desired membrane shape; and then

d. substantially removing the electron donor molecule from the system tocross-link the polyelectrolyte and recovering the thus prepared solidshaped structures.

Alternatively, the complexing reagent can be added to the solution ofanionic polyelectrolyte prior to the addition of the polyvalent cationto maintain the reaction product in solution in lieu of resolubilizingthe precipitate.

Method B comprises the sequential steps of:

a. fabricating a solution of an initially water soluble plasticizedanionic polyelectrolyte into the desired shape;

b. dipping the thus formed shape into an aqueous solution of apolyvalent metal cation to cross-link the anionic polyelectrolyte; and

c. recovering the thus prepared water insoluble cross-linked structure.

This material, methods for its preparation, and the use thereof, is thesole invention of Alan S. Michaels. It is more fully described andclaimed in copending application Ser. No. 248,168 (internal Docket No.Pm 5015) owned by the assignee of this invention, filed on April 27,1972, now U.S. Pat. No. 3,867,519 and generally described below.

Structures prepared from polymeric compositions of the above type arecharacterized by their ability to advantageously control the releaserate of drug through the material. When placed in contact with bodyfluids, e.g. tears, such polymeric structures sorb the tear fluid andswell by hydration to an extent governed by the degree of cross-linkingas determined by the polyvalent metal cation content and character. Aspreviously discusssed, control of drug release rate by a PermeationControl Release mechanism by means of swellable microporous hydrophilicmaterials is advantageous. This is so, since the release rate isdependent on the degree of swelling of the structure which can becontrolled over a wide range.

Among the anionic polyelectrolyte polymers which may be interacted toproduce the cross-linked structures which are useful in the presentinvention are those which are soluble in eye fluids and have asufficiently high molecular weight, typically at least 10,000, to besolid and capable of film formation, and containing a plurality offunctional groups which are reactive with the polyvalent metal cation toform a salt therewith. Preferably, the functional group is an alkalimetal or ammonium salt of a carboxylate, sulfate, sulfonate orphosphate. These functional groups can be characterized as beingdissociable anionic groups which are chemically bonded to the polymericchain. Exemplary of these polymers are: polysaccharides, e.g.K-carrageenin, pectinic acid, heparin sulfate, hyaluronic acid, heparin,natural gums such as algin, locust bean gum, agar, pectin, gum arabic,gum tragacanth; modified natural and synthetic polymers such ascarboxymethylcellulose, carboxymethyl starch, polystyrene sulfonic acid,polyvinyl sulfuric acid, poly(vinyl sulfonic acid), polyvinyl methylolsulfonic acid, hydrolyzed poly(vinyl acetate/maleic anhydride),polyvinyl ether-maelic anhydride, poly(ethylene-maleic anhydride),poly(acrylic acid), poly(methacrylic acid) and copolymers thereof withacrylic or methacrylic esters, poly(vinyl acetate), poly(vinyl alcohol),poly(vinyl chloride), styrene, and other materials of the same generaltype.

Preferred are the naturally occurring vegetable-derived water solublepolysaccharide polymers which are essentially devoid of animal or humantoxicity, and which decompose in the body into simple sugars.

The polyvalent metal cations which are interacted with the initiallywater soluble anionic polyelectrolytes include di, tri or tetra valentmetals such as copper, mercury, chromium, nickel, zinc, cobalt, ferricand ferrous iron, aluminum, tin, bismuth, calcium, magnesium, and thelike. It is to be understood that any polyvalent metal can be employedwhich is capable of coreacting with the polyelectrolyte to form a waterinsoluble precipitate and which is innocuous in the body. The anionassociated with the metal cation is preferably a halide, e.g. chloride;or sulfate, nitrate, although any innocuous ion can be used.

The complexing reagents employed in Method A are any of those materialswhich are capable of solubilizing or maintaining thepolyelectrolytepolyvalent cationic reaction product in solution so as toenable fabrication of the solution into the desired shape. Exemplary ofthese materials are primary, secondary and tertiary amines such as mono,di, or trimethyl amine, mono, di, or tri-ethanolamine, morpholine,pyridine, piperidine, piperazine, aniline, 2-methyl imidazole, ethylenediamine and higher polyethylene polyamines, and ammonia.

The complexing reagent must be present in solution in an amountsufficient to prevent precipitation of the reactive components. Thisamount will usually be about 5% by weight of the total solution,preferably at least 0.5% by weight. Although amounts as great as 50% ormore weight of the total solution may be used, it is unnecessary andfrequently undesirable to employ any more than the minimum required toprevnt precipitation of the polyelectrolytes. In general, theconcentration of the polyelectrolyte must be at least 0.5% by weight andpreferably above 1% by weight of the mixture in order to obtaincontinuous solids in the subsequent processing. Molar ratios of anionicpolyelectrolyte to polyvalent metal of from 1 to 10, and preferably from2 to 5, are satisfactory. The solution thus prepared is then caused togel by changing conditions so as to permit precipitation to occur bybreaking down the coordinate complex so as to cross-link the polymerwith metal. Gelation of the polymeric complex solute can be effected byreducing the effective concentration of the complexing reagent byneutralization thereof with acid, or removal in the case of volatilereagents by evaporation in the presence of heated moist air. Thestructure can be obtained by the usual process of casting, extruding themixture, or coating onto a suitable substrate and then drying the formedobject by suitable means.

In both Method A and Method B, the plasticizer, when included, ispreferably added to the structure when fabricating the solution into thedesired shape. Suitable plasticizers are described hereinafter.

The degree of cross-linking of the polymer by the metal ion can becontrolled by adjusting the ratio of metal to polymer in the initialsolution, thereby producing materials of varying hydrophilicities. Whenplaced in contact with a body fluid such as tears, these polymericstructures biodegrade by virtue of the gradual extraction and chelationof the polyvalent ion by endogenous proteins, polysaccharides, and othersubstances present in these fluids. By varying the degree ofcross-linking, the rate of drug release and biodegration can be variedover wide limits. If a natural gum (e.g. algin) is used in theformulation, after dissolution, enzymatic hydrolytic processes willcleave the solubilized polymer into innocuous sugars which are absorbedinto the eye and surrounding tissues.

4. - Cross-Linked Gelatin

Gelatin is obtained by the selective hydrolysis of collagen by meanswell known to those skilled in the art and comprises a complex mixtureof water soluble proteins of high molecular weight. As used herein, theterm cross-linked gelatin means the reaction product of gelatin or agelatin derivative with a cross-linking agent reactive with either thehydroxyl, carboxyl or amino functional groups of the gelatin moleculeand substantially unreactive with the peptide linkage of the gelatinmolecule, the product of reaction having an average molecular weightpreferably of from 20 to 50,000 between cross-links, although highervalues can be employed, and which product is biodegradable in theenvironment of the eye over a prolonged period of time.

Cross-linked gelatin materials are well known to those skilled in theart and can be prepared by reacting the cross-linking agent with gelatinunder suitable reaction conditions. The degree to which the gelatin iscross-linked is dependent upon the processing conditions employed tocarry out the reaction and markedly affects its characteristics withregard to the time required in order for the material to biodegrade inthe eye. The rate and, therefore, the degree of cross-linking of thegelatin is primarily determined by: (1) the effective concentration ofreactive groups present; (2) reaction time; (3) temperature at which thereaction is carried out; and (4) pH of the reaction environment. Thechoice of the particular conditions will of course depend on theproperties desired for the end product as hereinafter discussed.

Exemplary of suitable cross-linking agents are: aldehydes, such asmonoaldehydes, e.g. C₁ -C₄ aldehydes, e.g. propanal, acetaldehyde,formaldehyde, acrolein, crotonaldehyde, 2-hydroxy adipaldehyde;dialdehydes, such as glutaraldehyde, glyoxal; other aldehydes such asstarch dialdehyde, paraldehyde, furfural and aldehyde bisulfite additioncompounds such as formaldehyde bisulfite; aldehyde sugars, e.g. glucose,lactose, maltose, and the like; ketones such as acetone; methylolatedcompounds such as dimethylol urea, trimethylol melamine; "blocked"methylolated compounds such as tetra(methoxymethyl) urea, melamine; andother reagents such as C₁ -C₄ disubstituted carbodiimides; epoxides suchas epichlorohydrin, Eponite 100 (Shell); para-benzene quinone;dicarboxylic acids, e.g. oxalic acid; disulfonic acids, e.g. m-benzenedisulfonic acid; ions of polyvalent metals, e.g. chromium, iron,aluminum, zinc, copper; amines such as hexamethylene tetramine; andaqueous peroxydisulfate. See H. L. Needles, J. Polymer Science, PartA-1, 5 (1) 1 (1967).

Still another suitable method for cross-linking gelatin is that usingirradiation; see for example Y. Tomoda and M. Tsuda, J. Poly. Sci., 54,321 (1961).

The reactive groups present in gelatin, i.e. hydroxyl, carboxyl andamino functions are present per 100 grams of high quality gelatin in thefollowing approximate amounts: 100, 75 and 50 meq of each of thesegroups, respectively. The number of reactive sites do not varyappreciably from one gelatin to another, i.e. Type A or B gelatins,unless major hydrolytic breakdown has occurred. These quantities mayserve sa a general guide in determining the amount of cross-linkingagent to be used. However, any discussion of the chemical reactions ofgelatin must be made with regard to its very heterogeneous composition.Moreover, actual degradation rates are preferably determinedexperimentally as hereinafter exemplified in the Examples for a materialprepared under a given set of conditions. For example, usingformaldehyde as the cross-linking agent, concentrations thereof from0.01% to 60% by weight, based on the weight of the gelatin incombination with reaction times of 0.1 hours to 5 days and attemperatures of from 4.0° C to 35° C will yield suitable products, theexact combination of concentration, temperature and time depending onthe desired dissolution rate. General information on cross-linkedgelatin can be found in Advances in Protein Chemistry, Vol. VI, AcademicPress, 1951, "Cross Linkages in Protein chemistry", John Bjorksten.

5. - Other Bioerodible Materials

Other suitable materials which slowly bioerode in tear liquid may beclassified as follows: (a) structural proteins and hydrocolloids ofanimal origin; (b) polysaccharides and other hydrocolloids of plantorigin; and (c) synthetic polymers. Some of these matrix materials aresuitable as in their native form but others, particularly hydrocolloids,require insolubilization either by chemical modification, or physicalmodification, such as orientation, radiation cross-linking, etc.Exemplary of the first category are: native and modified collagens,muscle proteins, elastin, keratin, resilin, fibrin, etc. Exemplary ofpolysaccharides and plant hydrocolloids are: algin, pectin, carrageenin,chitin, heparin, chondroitin sulfate, Agar-agar, Guar, locust bean gum,gum arabic, gum Karaya, tragacanth, gum Ghatti, starch, oxystarch,starch phosphate, carboxymethyl starch, sulfaethyl starch, aminoethylstarch, amido ethyl starch, starch esters such as starch maleate,succinate, benzoate and acetate, and mixtures of starch and gelatin;cellulose and its derivatives such as modified cellulosics, such aspartially hydroxyethylated cotton obtained by the treatment of cottonwith ethylene oxide or partially carboxymethylated cotton obtained bythe treatment of cotton with caustic and choroacetic acid. Exemplary ofsynthetic polymers are: poly(vinyl alcohol), poly(ethylene oxide),poly(acrylamide), poly(vinyl pyrrolidone), poly(ethyleneimine),poly(acrylic acid) and poly(methacrylic acid) and copolymers thereof,poly(vinyl imidazole), poly(phosphate), synthetic polypeptides,polyvinyl alkyl ether, polyacryl-and polymethacrylamides, and copolymersof acrylamide and methacrylamide with up to 40% by weight of N-methylenebisacrylamide or N,N dimethylol urea; polyalkyl aldehydes, water solublehydrophilic polymers of uncross-linked hydroxyalkyl acrylates andmethacrylates, polyalkylene carbonates, and the like. The list isillustrative. Any bioerodible material which is compatible with the drugnon-toxic and which has the desired erosion and release rates can beused. Preferred, however, are the anionic polyelectrolytes (3) andcross-linked gelatin (4).

As illustrated in FIG. 3, the inner core 20 of the ocular insert is madefrom a non-release rate controlling matrix material having the drugdispersed therethrough. Since the function of the inner core is to actas the reservoir for the drug, it is fabricated, in each case, of amaterial that provides the optimal environment and releasecharacteristics for the drug being used. Materials suitable for formingthe inner core are those which are compatible and highly permeable tothe drug used and relatively rapidly bioerodible, exemplary of which areglycerinated gelatin, collagen, gum acacia, polyvinyl alcohol, polyvinylpyrrolidone, alginic acid and alkali metal salts of alginic acid, starchphosphate, starch and gelatin, linear polyacrylamides andpolymethacrylamides, and the like. In addition, any of the materialslisted above under paragraphs number (1) to (5) can be employed for thematrix material 20 illustrated in FIG. 3, consistent with commentspreviously made for selection of this material as related to the outerrelease rate controlling membrane material 22.

Any of the materials listed under paragraphs number (1) to (5) can beemployed for the matrix material 62 illustrated in FIG. 6 which housesthe reservoirs 61, consistent with comments previously made forselection of this material as related to the release rate controllingreservoir material.

Drug can be incorporated in the ocular insert in many ways. When theocular insert is in the form of a container, any of the encapsulation,bonding, and coating techniques and combinations thereof conventionallyused in the art can be employed. When the ocular insert is a matrix withthe drug dispersed therethrough, it can be fabricated by adding the drugto the monomers prior to polymerization; adding the drug to the polymerin liquid form, casting or molding and curing; or by impregnating thepolymeric material, either before or after shaping to the form of theocular insert, with the drug. When lamination is employed to fabricatethe insert, the device may comprise a sheet of inner core materialsandwiched between two sheets of outer layer material. To enhanceadhesion between the layers, the inner core can be perforated orembossed. When the matrix material comprises a plurality of reservoirmicrocapsules they can be mixed with the matrix forming material, whichcan be in solid, semi-solid, or liquid form at the time of mixing, andthen distributed therethrough by conventional methods, such asballmilling, calendering, stirring, shaking, and the like. Where thereservoirs are generally compatible with monomers or prepolymers used toform the matrix, the reservoirs can be added at this earlier stage offormation, and the matrix formed in situ. The matrix material, howevermade and having the reservoirs distributed therethrough, can then beformed to a given drug design by molding, casting, pressing, extruding,drawing, rotational molding, compression and transfer molding, or likeprocesses of manufacture. Also, depending on the material used to formthe matrix, the monomers may be cured at this stage of manufacture. Theability to design and shape the matrix into highly reproducible shapesof controllable composition, readily results in fabrication of drugdelivery devices with controlled characteristics. Other standardprocedures, well known to those skilled in the art, can be used tofabricate the drug delivery devices of the invention.

The bioerodible release rate controlling material can have incorporatedtherein plasticizers, preservatives or other conventional additivesemployed in dosage forms. Exemplary plasticizers suitable for employmentfor the present purpose are the pharmaceutically acceptable plasticizersconventionally used, such as diethyl adipate, di-isobutyl adipate,di-n-hexyl adipate, di-isooctyl adipate, di-n-hexyl azelate,di-2-ethylhexylazelate, ethylene glycol dibenzoate, acetyl tri-n-butylcitrate, expoxidized soy bean oil, glycerol monoacetate, diethyleneglycol dipelargonate, propylene glycol diluarate, iso-octyl palmitate,triphenyl phosphate, and the like. In addition, binding agents ordisintegrating agents to regulate or to facilitate the bioerosion of thedevice can be employed. Exemplary of these materials are glycerin,dextrose, sorbitol, mannitol, sucrose, poly(ethylene glycol),monoglyceryl esters of fatty acids, methylcellulose, starch, and thelike. The proportion of agent used will vary within broad limitsdepending upon the rate of disintegration desired, as well as upon thecharacteristics of the medicament involved. In general, about 0.01 partsto about 10 parts by weight for each part by weight of the medicamentcan be used, depending on the agent.

Enzymes can be incorporated into the release rate controlling materialin order to further control the rate of bioerosion of the membrane ormatrix materials of the device. Among the enzymes which can be includedare pepsin, trypsin, ficin, papain, aminopeptidase, pectase, invertase,takadiastrase, pancreatin lactase, alpha amylase, beta amylase, andcellulase. Typical combinations of enzyme and material include:cellulase with cellulose and its derivatives; takadiastase with starch;aminopeptidase with polypeptides.

As previously discussed, devices of this invention are designed todispense a metered amount of drug from the reservoir to the eye over aprolonged period of time, primarily through a Permeation or ErosionControl Release mechanism. Moreover, as heretofore indicated, in orderto design these devices it is necessary to select materials having boththe appropriate drug release rate characteristics and erosion rates.Those skilled in the art can readily determine the rate of permeabilityof drug through a material or selected combinations of polymericmaterials. Standard methods of determining passage of drugs through drugpermeable materials are exemplified in Encyl. Polymer Science andTechnology, Vol. 5 and 9, pp. 65-85 and 795-807, 1968, and the referencecited therein; U.S. Pat. No. 3,279,996; Folkman and Edmonds, CirculationResearch, 10:632, 1962; Folkman and Long, J. Surg. Res., 43:139, 1964;and Powers, J., Parasitology 51:53 (April 1965), No. 2 Section 2.

The erosion rate of a material can be determined by methods exemplifiedin the examples set forth hereinafter, or can be conducted withapparatus similar to the tablet disintegration apparatus described inU.S.P. XVII. Simulated tear fluid, e.g. saline fluid, is used in thetest. The device is placed in the apparatus and initially contacted withsimulated saline fluids for set periods of time. The weight loss of thedevice is then determined. The saline fluid is then removed and thecourse of the disintegration of the device is followed over the timecourse of the test by periodically determining the weight loss of thedevice or by measuring the amount dissolved by other suitable means,e.g. spectrophotometrically. The drug release rate is also determined inthis test by periodically assaying the amount of drug that dissolves inthese fluids over the course of the test.

It is intended that devices of this invention continuously dispensecontrolled amounts of drug to the eye over prolonged periods of time,that is, from periods ranging from 8 hours to 30 or more days. Thematerial selected must therefore have an erosion rate in the eye,suitably modified if necessary, by the addition of additives, ashereinbefore mentioned, which is dependent upon the time periodselected, as well as whether it is to be used as a rate controllingmatrix of the type illustrated in FIGS. 5 or 7, or a rate controllingmembrane of the type illustrated in FIGS. 3 and 4, or for themicrocapsules of the type illustrated in FIG. 6, or a non-ratecontrolling material of the type illustrated in FIGS. 3 or 6, withregard to comments earlier made concerning the function of each of thesematerials. Generally, the following material erosion rates aresatisfactory, with the exact rate selection dependent upon designconsiderations previously set forth:

    ______________________________________                                                        Illustrative Erosion                                                          Milligrams/Day                                                Non-release Rate                                                              Controlling Matrix                                                            Material          0.5 - 20                                                    Release Rate Controlling                                                      Membrane or Matrix                                                            Material          0.1 - 15                                                    ______________________________________                                    

From the foregoing, it is apparent that it is preferred to place theocular device in the sac of the eye, either 7 or 11, bounded by thesurfaces of the sclera of the eyeball and conjunctiva of the lid. Thereason for this is the fact that obstruction with vision is avoided.Moreover, the scleral area of the eye is less sensitive to pain than areother portions of the eye. It is, however, contemplated herein that ifdesired, the device can be placed over the corneal portion 5 of the eye.

Insertion of the insert 12 into the eye can be satisfactorilyaccomplished by mounting or grasping the device by means of a suitableholder, which optionally may include a minute suction cup for engagingthe outer surface of the insert. The holder may be one of the severaltypes commonly used to insert and remove corneal contact lenses,artificial eyes, and the like. Further, the present inventioncontemplates the use of an indicator dye in the drug or material of theinsert, or both, to serve as a visual indication as to the supply ofdrug within the device or the device itself in the eye. For thispurpose, a small amount of methylene blue or any suitable dye materialcan be used.

The ocular inserts are suitably packaged using a drug and moistureimpermeable packaging material such as the foil - polylaminates, e.g.aluminum foil - polyethylene laminate or aluminum foil - polyester(Mylar) - laminate. While the inserts can be packaged either wet or dry,the latter becomes mandatory when certain bioerosion processes areinvolved. More specifically, when the bioerosion process is effected bydissolution or hydrolysis, dry packing, e.g. vacuum packing, isrequired.

The ocular devices are preferably sterilized prior to insertion in theeye. The sterilization can be effected prior to packaging or afterpackaging. Suitable sterilization methods such as the use of radiationor ethylene oxide can be satisfactorily employed. Details for thesemethods and others are set forth in Remington's Pharmaceutical Sciences,Vol. XIV, 1970, pp. 1501-1518.

For a more complete understanding of the nature of this invention,reference should be made to the following examples which are givenmerely as further illustrations of the invention, and are not to beconstrued in a limiting sense. All parts are given by weight, unlessstated to the contrary.

Example 1

A bioerodible ocular insert containing hydrocortisone is prepared in thefollowing manner:

A. Preparation of zinc alginate -

1. Seven grams of sodium alginate (Keltone, Kelco Co., KT-9529-21) isdissolved in 350 ml of distilled water by means of efficient stirring,to yield a slightly viscous solution.

2. In a separate preparation, 10 grams of zinc chloride is dissolved in600 ml of distilled water and the pH is adjusted to 3 by drop-wiseaddition of concentrated hydrochloric acid.

3. The zinc chloride is transferred into a gallon-size Waring blenderand to this solution is added in small proportions the sodium alginatesolution under moderate agitation. After the addition is complete, themixture is vigorously stirred for 10-15 minutes, transferred to a glasscontainer and allowed to stand overnight.

4. The precipitate is then transferred to a large size chromatographiccolumn and washed continuously with distilled water to a negative silverchloride test (or to the same conductivity reading as distilled water).The aqueous suspension of the sodium chloride-free zinc alginate isisolated by lyophilization and vacuum-dried at 40° C overnight.

B. Preparation of hydrocortisone ocular insert -

1. The mixture containing 1.5 grams of micronized hydrocortisone in 3.5grams of glycerine is homogenized by means of a suitable colloid mill orby simple grinding of the mixture with mortar and pestle.

2. The resulting white paste is slowly poured into a Waring blendercontaining 100 ml of 1.2% ammonium hydroxide solution under vigorousagitation. To this suspension is, then, added 5 grams of zinc alginatepreviously prepared, and the vigorous agitation is continued until thecomplete dissolution of the zinc alginate results; if marked thickeningoccurs, more ammonia solution can be added.

3. The viscous dispersion of (5) is drawn on a glass plate with a wetthickness of ca. 10 mils. The cast plate is placed in a circulatingstream of warm, moisturized air at 40° C, and allowed to dry thoroughly.

4. The resulting film is removed from the plate by stripping, and ispunch-cut into desired shape and size. For example, the circular insertdevice of 6.1 mm diameter and 3 mil thickness contains about 0.45 mg ofhydrocortisone. When inserted in a monkey's eye, the resulting insertreleases the drug over a two-day period at the termination of which theinsert has totally eroded in the eye.

Example 2

A. Preparation of sodium alginate-hydrocortisone acetate ocular insert -

1. A paste containing 3.2 grams of micronized hydrocortisone acetate and5.6g glycerine is prepared by grinding the mixture with mortar andpestle (or with colloid mill).

2. The paste is transferred into a Waring blender containing 0.03 gramTween 80 (Atlas Chemical Industries) and 150 ml distilled water. To thisfine particle suspension is added 7.5 grams of sodium alginate undervigorous stirring. Alternatively, the Premier-Dispersator (Premier MillCorp.) may be used for this purpose. If necessary, the whole content maybe transferred to a widemouth bottle and placed on a variable speed jarmill (Norton Co.) for 12 hours or to complete sodium alginatedissolution.

3. The film is then prepared by casting the mixture on a clean glassplate, and drying it at 40° C for 16 hours. A 125 mil cast of thissolution gives about 10 mil-thick dry film.

B. Insolubilization -

1. The plasticized sodium alginate-hydrocortisone acetate film is dippedinto 5.5% zinc chloride solution (pH adjusted to 4.5) for 5 hours. Thefilm is then washed twice by immersion in a stirred 50% glycerine bathor until the final washing gives a negative silver chloride test. Thefilm is then air-dried at room temperature, and punch-cut into circulardisks 6 mm in diameter.

2. An aluminum alginate-hydrocortisone acetate film can also be preparedfrom the plasticized sodium alginate film by a method analogous to thatof zinc alginate film described above using 10% alum (KAl(SO.sub. 6)₂)solution (pH 3.1).

When inserted in the sac of a human eye, the above prepared devicesrelease the drug at a controlled rate. The inserts completely bioerodein the eye at the termination of the therapeutic program. Table I, whichfollows, characterizes the devices prepared.

                  TABLE I                                                         ______________________________________                                        CHARACTERISTICS OF HYDROCORTISONE ACETATE                                     CONTAINING METAL-ALGINATE COMPLEXES                                                          Zn-Alginate                                                                             Al-Alginate                                                         Hydrocortisone                                                                          Hydrocortisone                                                      Acetate   Acetate                                              1.  Hydrocortisone   30/70       30/70                                            acetate content                                                               (H.C.Ac./Alg.)                                                            2.  Cross-linking conditions                                                                       5.5% ZnCl.sub.2                                                                           10% Alum                                                          pH 4.5      pH 3.1                                                            5 hrs.      5 hrs.                                       3.  Tackiness        non-tack    non-tack                                     4.  Color, appearance, etc.                                                                        white, smooth                                                                             white, smooth                                5.  Cohesiveness (or intact-                                                                       fair        good                                             ness on swelling, after                                                       3-4 hrs.)                                                                 6.  Time to erosion (days)                                                                         6 days      >10 days                                     7.  Hydrocortisone acetate                                                                         7           1.5                                              release μg/hr                                                          ______________________________________                                    

Example 3

Cross-linked gelatin ocular inserts containing hydrocortisone are usedfor the treatment of eye inflammation and are prepared as follows.

A phosphate buffer is prepared by addition of one liter of distilledwater to 7.1 grams of disodium hydrogen phosphate and 6.9 grams ofsodium dihydrogen phosphate monohydrate. The pH is determined to be 6.8.A solution of 0.9 gm glycerin in 40 ml of the phosphate buffer isprepared and 0.15 gm chlorobutanol is added. Upon heating to 90° C andstirring the chlorobutanol is dissolved. Nine grams of gelatin (AtlanticPharmagel 250 Bloom Type A USP) is added slowly with stirring to theabove prepared buffer solution at 90° C. Alternatively, to be moreefficient, the gelatin can be added to the vigorously stirred buffersolution after it is cooled to room temperature and then the mixtureheated at 90° C until solution is complete.

To suspend the hydrocortisone in the gelatin solution, 3.1 grams ofhydrocortisone (Calibiochem) is first ground in a mortar and pestle,then 10 microliters of Tween 80 (Atlas, USP grade) are added and groundinto the hydrocortisone. This mixture is suspended in five ml ofphosphate buffer with thorough stirring and the resultant mixture addedimmediately to the stirred gelatin solution as it cools to approximately50° C. The final mixture is stirred thoroughly for four minutes untilthe temperature falls to 40° C. It is then poured onto a sheet ofpolyvinyl chloride which is flattened against a glass plate aftermoistening the back with water. A film is cast with a doctor's bladeadjusted for a wet thickness of 40 mils. The film is allowed to dry bystanding at room temperature one day.

To cross-link the gelatin a solution of 1% formaldehyde by weight isprepared by addition of 13.1 grams of 38% formaldehyde reagent to 487grams phosphate buffer (pH 6.8). This volume is sufficient for thetreatment of the amount of film prepared as described above. The gelatinfilms are submerged in this buffered formaldehyde solution for 20minutes at room temperature, the solution is discarded, and the filmsare rinsed with water quickly and soaked in ice water for 2 hours. Afterremoval from the ice water and overnight standing at room temperature,the films are prepared for cutting by dipping in water for a fewminutes. Excess water is removed and the inserts are cut from theflexible film with an illiptical die and dried at room temperature forseveral hours, then packaged in polyethylene-foil laminate packets. Theellipsoidal ocular inserts are 11.5 millimeters in length and 0.5millimeter thick. When inserted in the sac of a human eye, the resultinginsert relatively uniformly releases the drug over a period of 4 days,at which time the insert completely bioerodes.

Example 4

The following experiments illustrate the effect of the cross-linkingagent, its concentration and time of treatment with blank gelatininserts with regard to material bioerosion time.

Experimental Procedure

Standard gelatin formula:

18.0 gms Pharmagel Bloom Type A

1.8 gms Glycerin (Plasticizer)

0.3 gm Chlorobutanol (Preservative)

90 ml Phosphate Buffer (0.05M., pH 7.00)

Dissolve glycerin and chlorobutanol in preheated and cooled buffer. Addgelatin; dissolve by heating the solution. Films are made using the thinlayer spreader yielding films that are approximately 17-19 mils thick.After spreading films, they are dried for 4 to 5 hours at roomtemperature.

The films are soaked in specific aldehyde concentration for a particulartreatment time at 25° C. The gelatin films are washed with colddistilled water to remove excess aldehyde and are washed until the washgives no color when tested with a chromo-tropic acid solution.

Alternatively, the cross-linking agent can be admixed with the gelatinprior to forming the film.

Inserts are made from a punch 11.5 × 4 mm, and one insert is placed in aglass-stoppered, graduated centrifuge tube containing 5 ml of 0.05Mphosphate buffer, pH 7.00, at 37° C. The rate of dissolution isdetermined at 37° C according to the following procedure.

The insert is removed from the solution at selected intervals and thebuffer solution is analyzed for gelatin content. The insert is thenplaced in another stoppered tube containing a fresh solution of bufferwhich is placed in the water bath. The procedure is repeatedly carriedout.

The buffer solution that was removed is adjusted to 5 ml, if necessary,and read in Cary 14 Spectrophotometer set at wavelength 230 mμ. Readsample versus a blank buffer solution. The absorbencies are recorded andtotaled at each time interval. The percentage of gelatin released isobtained: ##EQU1##

A. Effect of formaldehyde concentration and time of treatment on thetime of complete dissolution.

                  TABLE I                                                         ______________________________________                                        Treatment with Formaldehyde                                                   Formaldehyde                                                                              Time of       Time for Complete                                   Concentration (%)                                                                         Treatment (hrs)                                                                             Dissolution (hrs)                                   ______________________________________                                        0.05        .167          5                                                               2.0           51                                                              7.0           91                                                              24.0          151                                                 1           5.0           119                                                 2           .083          16                                                              .167          16                                                              2.0           197                                                             7.0           221                                                             24.0          241                                                 2.5         .083          16                                                              .167          48                                                  3           .083          36                                                              .167          46                                                              .250          96                                                  5           .167          48                                                              .25           72                                                              .67           104                                                             2.0           197                                                             5.0           175                                                             7.0           221                                                             24.0          253                                                 6           .083          49                                                  8           .083          49                                                  10          .083          55                                                              .167          72                                                              .250          96                                                              .167          72                                                              .250          96                                                              2.0           197                                                             5.0           216                                                             7.0           216                                                             24.0          217                                                 20          .167          96                                                              .250          168                                                             .670          168                                                 37          .167          168                                                             .250          168                                                             .670          168                                                 ______________________________________                                    

B. Effect of glutaraldehyde concentration and time of treatment on thetime for complete dissolution of film (Table II).

                  TABLE II                                                        ______________________________________                                        Treatment with Glutaraldehyde                                                 Glutaraldehyde                                                                            Time of       Time for Complete                                   Concentration (%)                                                                         Treatment (hrs)                                                                             Dissolution (hrs)                                   ______________________________________                                        0.01        7             78                                                  0.05        .083          42                                                              .167          42                                                              7.0           334                                                 0.025       .167          192                                                             5.0           358                                                 ______________________________________                                    

EXAMPLE 5

The following experimental procedure is used to determine the rate ofrelease of hydrocortisone from an ocular insert.

Gelatin films containing 10% hydrocortisone acetate, based on totalweight dry solids, are cross-linked in 1% aqueous formaldehyde for 20minutes, immersed in ice water, and allowed to dry. Ocular insertshaving an area of 1.1 cm² are cut from the films. The inserts are placedin open mesh Dacron packets which are suspended on a nichrome wire in0.9% aqueous NaCl in volumetric flasks of appropriate size at 37° C,placed on a Burrel shaker, and agitated for varying periods. At the endof the indicated intervals, the packets are transferred to anothervolumetric flask and the washes are saved for analysis.

The saline washes are extracted by pouring them into a separatory funnelof appropriate volume, adding 40 ml diethyl ether to the volumetricflask, transferring the ether to the separatory funnel, shaking 100times. After the separatory funnel is allowed to stand for 20 minutes,the saline layer is removed through the stop-cock, and the ether phasepoured into a 25 × 200 mm culture tube. The saline phase is thentransferred to the separatory funnel, 10 ml diethyl ether is added andthe funnel shaken 100 times again. After allowing the separatory funnelto stand for 20 minutes, the saline phase is removed through the funnelstop-cock, and the ether phase is combined with the previous 40 mlextract by pouring it from the top of the funnel. The funnel is rinsedtwice with 3 ml aliquots of diethyl ether, which is likewise transferredto the culture tube. The tube is placed in a mineral oil bath at about35° C and the sample allowed to evaporate to dryness.

The residue is dissolved in 5 ml methanol, the tube fitted tightly witha black rubber stopper, shaken for 1 minute, allowed to stand for 2hours at room temperature, shaken again for 1 minute, and transferred toa one cm spectrophotometer cell.

The resulting solution is scanned on a Cary-14 spectrophotometer from λ= 250 mμ to λ = 235 mμ. Between samples, the sample cells were rinsedtwice with methanol, once with acetonitrile, and once again withmethanol. The sample cell is then filled with methanol, and balancedversus methanol at λ = 242 mμ.

Calculations are made as follows: ##EQU2##

The data obtained over the first 71/2 hours is as follows:

    ______________________________________                                                         Total Cumulative                                             Time (hrs)       Amt Released (mg)                                            ______________________________________                                         1/2              175                                                         11/2              470                                                         21/2              750                                                         4                1050                                                         71/2             1500                                                         ______________________________________                                    

Although release studies were terminated after 71/2 hours, datacollected in subsequent studies indicate eventual complete release ofdrug.

EXAMPLE 6

Correlation between in vitro and in vivo bioerosion times in a rabbit'seye of a cross-linked gelatin matrix prepared in Example 1 as a functionof formaldehyde concentration and time of treatment.

                  TABLE III                                                       ______________________________________                                                               Time for   Correlated                                              Time of    Complete   In Vitro                                    Formaldehyde                                                                              Treatment  Bioerosion Bioerosion                                  Concentration (%)                                                                         (min)      (hrs)      (hrs)                                       ______________________________________                                         5          40         90          96                                          6           5         18                                                                  6         18                                                                 20         60          60                                         10          20         24          70                                                     40         96         120                                         37          20         96         120                                         ______________________________________                                    

EXAMPLE 7

Results of a study of the erosion time of gelatin films treated withformaldehyde are set forth below.

Formaldehyde polymerization Gelatin films without drug are each treatedwith formaldehyde solutions buffered to pH 7.0, (3 mg of gelatin per 1cc of solution) under the conditions shown in Table I. Aftercross-linking, the films are placed in several 100 cc ice water washesfor 20 hours to remove free formaldehyde. The films are removed, driedat room temperature, and sterilized with ethylene oxide for 4 hours.

Results in TABLE 1 below demonstrate that the polymerization reaction isconcentration, time and temperature dependent.

                                      TABLE I                                     __________________________________________________________________________    Formaldehyde Polymerization of Gelatin (without drug)                         A.                                                                              Effect of HCHO and Reaction Time                                                                Erosion at 37° C                                          Reaction     Daily   Total                                             (HCHO) Time  Temperature                                                                          Rate (est.)                                                                           Time                                              __________________________________________________________________________    0.25%  20 min  25° C                                                                         33%   3 days                                            0.50%  20 min  25° C                                                                         19%   5 days                                            0.75%  20 min  25° C                                                                         7.5%  Over 1 week                                       1.0%   20 min  25° C                                                                         7.5%  Over 1 week                                       0.25%  60 min  25° C                                                                         25%   4 days                                            0.50%  60 min  25° C                                                                          5%   Over 1 week                                       0.75%  60 min  25° C                                                                          4%   Over 1 week                                       B.                                                                              Effect of Lowering Reaction Temperature                                     1.0%   1/3 hour                                                                            25° C                                                                         33%     3 days                                            2.0%   1  hour                                                                             4.5° C                                                                        25%     4 days                                            2.0%   6  hour                                                                             4.5° C                                                                         3%     Over 1 week                                       __________________________________________________________________________

EXAMPLE 8

Erosion times for hydrocortisone acetate inserts as a function offormaldehyde and drug concentrations, reaction temperatures and timewere studied.

Experimental

Gelatin (gelatin used is Pharmagel A grade, Atlantic Gelatin) filmscontaining 80% by dry weight hydrocortisone acetate and 60% by dryweight hydrocortisone acetate were prepared by casting well stirredslurries of the drug in gelatin solutions onto a cellulose triacetatesurface. Ocular insert sized pieces of this film were cross-linked informaldehyde solutions at the indicated concentrations, all buffered atpH 7.0, using the same volume of formaldehyde solution for the sameamount of film in each case. They were then washed in ice water for 18hours to remove residual formaldehyde, dried at room temperature, andsterilized with ethylene oxide for 16 hours. To obtain drug release rateand insert erosion time, these were then placed in 150 milliliters ofsaline at 37° C and changed every few hours to fresh solutions. Selectedsamples of these solutions were analyzed for hydrocortisone acetatecontent by extracting with ether, evaporating the ether, dissolving theresidue in methanol and either measuring the absorbency at 242millimicrons or analyzing by liquid chromatography.

Results - Erosion Time and Drug Release

                                      TABLE I                                     __________________________________________________________________________    EROSION TIMES FOR HYDROCORTISONE ACETATE INSERTS                              AS A FUNCTION OF FORMALDEHYDE AND DRUG CONCENTRATIONS, REACTION               TEMPERATURES AND TIME                                                                            Total Erosion Time in Days                                                    After HCHO Treatment For:                                                Reaction                                                        %HCHO                                                                              %Drug/%Gelatin                                                                         Temp.                                                                              1/3 Hr.                                                                             1 Hr.  4 Hr.                                                                              6 Hr. 8 Hr.                              __________________________________________________________________________    0.05 80/20    25° C                                                                       --    --     3    4     5 +                                0.05 60/40    25° C                                                                       1-2 days                                                                            1-2 days    5 days                                   0.05 80/20    25° C                                                                       --    0.1 days    *6 + days                                0.25 60/40    25° C                                                                       1-2 days                                                                            6 days      6 + days                                 0.25 80/20    25° C                                                                       --    4 1/3 days  6 + days                                 0.50 60/40    25° C                                                                       5 days            --                                       0.50 80/20    25° C                                                                       --    6 + days    6 + days                                 0.75 60/40    25° C                                                                       6 + days                                                                            6 + days    --                                       1.0  80/20    25° C                                                                       --    6 + days    6 + days                                                    --                                                         0.25 60/40    4.5° C                                                                      --    --          5 days                                   0.25 80/20    4.5° C                                                                      --    0.1 days    6 + days                                 0.50 60/40    4.5° C                                                                      --    6 + days    --                                       0.50 80/20    4.5° C                                                                      --    4.3 days    5 days                                   0.75 80/20    4.5° C                                                                      --    6 + days    6 + days                                 1.0  80/20    4.5° C                                                                      --    6 + days    6 + days                                 __________________________________________________________________________     *6+ days = Inserts lasting longer than 6 days when test was stopped.     

                                      TABLE II                                    __________________________________________________________________________    HYDROCORTISONE ACETATE RELEASE RATES FROM                                     ERODIBLE GELATIN INSERTS                                                                       Drug Release Rate (μg/hr) After:                          Polymerization Conditions                                                                     Hours                    Total Erosion                        % Drug %HCHO ° C                                                                   Time:                                                                             18-24                                                                              24-29                                                                              42-47                                                                              66-71                                                                              90-95                                                                              Time                                 __________________________________________________________________________    80 0.50                                                                              25   1 hour                                                                            66   --   47   43   34   7 + days                             60 0.50                                                                              25   1 hour                                                                            --   70   --   --   --   7 + days                             80 0.75                                                                              25   1 hour                                                                             0   --   43   31   35   7 + days                             60 0.75                                                                              25   1 hour                                                                            --   59   --   --   --   7 + days                             80 0.50                                                                              4 1/2                                                                              1 hour                                                                            --   --   --   46   96   4 days                               80 0.50                                                                              4 1/2                                                                              1 hour                                                                            --   --   --   50   70   4 days                               __________________________________________________________________________

EXAMPLE 9

Five hundred grams of chloramphenicol of a particle size of 50 micronsis encapsulated with polylactic acid polymer of molecular weight 50,000according to the following procedure. Two hundred and fifty grams of thepolylactic acid is dissolved into 2 liters of chloroform. Thechloramphenicol particles are coated by polylactic acid using Wursterair suspension technique. The coat thickness is determined to be 30microns thick.

A phosphate buffer is prepared by addition of one liter of distilledwater to 7.1 grams of disodium hydrogen phosphate and 6.9 grams ofsodium dihydrogen phosphate monohydrate. The pH is determined to be 6.8.A solution of 0.9 gram glycerin in 40 ml of the phosphate buffer isprepared and 0.15 gram chlorobutanol is added. Upon heating to 90° C andstirring, the chlorobutanol is dissolved. Nine grams of gelatin(Atlantic Pharmagel 250 Bloom Type A USP) is added slowly to the aboveprepared buffer solution at 90° C.

Three grams of the chloramphenicol microcapsules are dispersed in theabove prepared gelatin solution as it cools to approximately 50° C. Thefinal mixture is stirred thoroughly for 4 minutes until the temperaturefalls to 40° C. It is then poured onto a sheet of polyvinyl chloridewhich is flattened against a glass plate after moistening the back withwater. A film is cast with a doctor's blade adjusted for a wet thicknessof 40 mils. The film is allowed to dry by standing at room temperature 1day.

To cross-link the gelatin a solution of 1% formaldehyde by weight isprepared by addition of 13.1 grams of 38% formaldehyde reagent to 487grams phosphate buffer (pH 6.8). This volume is sufficient for thetreatment of the amount of film prepared as described above. The gelatinfilms are submerged in this buffered formaldehyde solution for 20minutes at room temperature, the solution is discarded, and the filmsare rinsed with water quickly and soaked in ice water for 2 hours. Afterremoval from the ice water and overnight standing at room temperature,the films are prepared for cutting by dipping in water for a fewminutes. Excess water is removed and the inserts are cut from theflexible film with an elliptical die and dried at room temperature forseveral hours. The ellipsoidal ocular inserts are 11.5 millimeters inlength and 0.5 millimeter thick. When inserted in the sac of a humaneye, the resulting insert continuously releases the drug at a controlledrate over a period in excess of 3 days and completely bioerodes in theeye thereafter.

EXAMPLE 10

The procedures and methods employed in Example 9 are repeated, however,substituting 3 grams of epinephrine microcapsules having an averageparticle size of 30 microns, coated to a 10 micron thickness withcholesterol palmitate for the 3 grams of chloramphenicol microcapsulesused in Example 9. When placed in the eye, the above prepared insertcontinuously releases the drug at a controlled rate over a prolongedperiod of time and therafter completely bioerodes in the eye.

EXAMPLE 11

A bioerodible ocular insert containing hydrocortisone acetate isprepared in the following manner:

1. Ten grams of polyvinyl alcohol (duPont Elvanol 72-60, 99-100%hydrolyzed, molecular weight 250,000) is dissolved in 100 ml ofdeionized water at 90° C by means of Premier Dispersator (Premier MillCorp.).

2. Into this hot solution is added slowly the hydrocortisone acetatepaste which is prepared by mixing 2 grams of micranized hydrocortisoneacetate, 5 grams of glycerine, and 0.01 gram of Tween 80 (Atlas) incolloid mill. The mixture is stirred until a homogeneous dispersion isobtained.

3. The presence of any bubbles in the mixture may be removed by means ofcentrifigation (N.B. prolonged centrifigation causes the settlement ofhydrocortisone acetate) while the dispersion is cooled.

4. The dispersion is then drawn on a glass plate. The coated plates arethoroughly dried in a circulating stream of warm air at 50° C.

5. the resulting film is stripped off from the glass plate and punch-cutinto circular inserts of 6 mm diameter and 0.5 mm thick. The devicecontains about 5 mg of hydrocortisone acetate per square centimeter.When inserted in a monkey's eye, the insert continuously releases thedrug at a controlled rate over a prolonged period of time, andthereafter completely bioerodes in the eye.

EXAMPLE 12

A bioerodible ocular insert containing chloramphenicol is prepared inthe following manner:

1. Poly(lactic acid) is prepared from the cyclic lactide as described byR. K. Kulkarni, E. G. Moore, A. F. Hegyelli, and F. Leonard in J. ofBiomed. Mater., Res. 5, 169-181 (1971).

2. A solution of the polymer is prepard by dissolving 10 grams of thepolymer in 100 ml methylene chloride.

3. To this solution is added 2.0 grams of chloramphenicol and thesolution stirred until it is homogeneous.

4. The polymer and drug composition is drawn on a glass plate. Thecoated plate is first dried in air at room temperature and then placedin an oven at 40° C and allowed to dry thoroughly.

5. The resulting film is punch-cut into circular inserts of 6 mmdiameter and 0.5 mm thick. The device contains about 8 mg ofchloramphenicol per square centimeter. When inserted in a monkey's eye,the insert continuously releases the drug at a controlled rate over aprolonged period of time, and thereafter completely bioerodes in theeye.

EXAMPLE 13

A bioerodible ocular insert containing sulfathiazole is prepared in thefollowing manner:

1. Poly(sebacic anhydride) is prepared from 20 grams of sebacic acid and100 ml acetic anhydride as described in the book "Collected Papers ofWallace Hume Carothers", Interscience, New York, 1940, edited by H. F.Mark and S. B. Wentby.

2. Ten grams of the finely powdered polymer is then intimately mixedwith 2.0 grams of sulfathiazole, the mixture compression molded on aCarver press, held at 90° C and 10,000 psi for 1 minute and then cooledto room temperature without releasing the pressure.

3. The resulting film is punch-cut into circular inserts of 6 mmdiameter and 0.5 mm thick. The device contains about 8 mg ofsulfathiazole per square centimeter. When inserted in a monkey's eye,the insert continuously releases the drug at a controlled rate over a14-day period, and thereafter completely bioerodes in the eye.

EXAMPLE 14

A bioerodible ocular insert containing pilocarpine is prepared in thefollowing manner:

1. Poly(glycolic acid) is prepared from hydroxyacetic acid as describedby N. A. Higgins in U.S. Pat. No. 2,676,945 (Apr. 27, 1954).

2. A film having a thickness of 3 mils is compression molded on a Carverpress held at 240° C and 20,000 psi.

3. A film of drum-containing core is prepared by:

a. Dissolving 10 grams of poly(vinyl alcohol), duPont Elvanol 52-22 in90 ml of distilled water maintained at 70° C.

b. Cooling this solution, adding 20 grams of pilocarpine free base andstirring until solution is complete.

c. Drawing this solution on a glass plate to provide a film having athickness of 6 mils and drying in air at room temperature for 24 hours.

d. Punch-cutting the pilocarpine-containing films into circular shapesof 4.5 mm diameter.

4. The circular core is placed between two sheets of poly(glycolic acid)prepared under (2) and heat sealed by a circular die of 6 mm diameter.The die temperature is 250° C and contact time 1 second. When insertd ina monkey's eye, the insert releases the drug over a prolonged period oftime, and thereafter completely bioerodes in the eye.

EXAMPLE 15

Other ocular inserts of the type set forth in FIG. 3 include devicescomprising the following combinations of drug, inner reservoir and outerrate controlling membrane:

1. An inner reservoir of hydrocortisone acetate dispersed in apoly(vinyl alcohol) matrix with the outer rate controlling membranematerial being cross-linked gelatin.

2. An inner reservoir of chloramphenicol dispersed in a chitin matrixwith polylactic acid being the outer rate controlling membrane material.

3. An inner reservoir of pilocarpine dispersed in a poly(vinylpyrrolidone) matrix with the outer rate controlling membrane materialbeing ethylene-maleic anhydride.

While there have been described and pointed out the fundamental novelfeatures of the invention as applied to preferred embodiments, thoseskilled in the art will appreciate that various modifications, changesand omissions in the form and details of the ocular insert described canbe made without departing from the spirit of the invention.

What is claimed is:
 1. A bioerodible ocular device for the controlledcontinuous administration of a predetermined dosage of drug to the eye,comprising (1) an inner reservoir containing a drug formulation confinedtherein, and (2) an outer membrane formed from drug release ratecontrolling bioerodible material surrounding the inner reservoir, themembrane being permeable to passage of drug, but at a lower rate thanthrough the inner reservoir, the device being of an initial shape whichis adapted for insertion and retention in the sac of the eye bounded bythe surfaces of the bulbar conjunctiva of the sclera of the eyeball andthe palpebral conjunctiva of the lid, whereby release of drug from thedevice to the eye is effected primarily by a permeation control releasemechanism in which the outer membrane continuously meters the flow of atherapeutically effective amount of drug from the reservoir to the eyeat a controlled rate over a prolonged period of time, and wherein thedevice bioerodes in the environment of the eye concurrently with thedispensing or at a point in time after the dispensing of thetherapeutically desired amount of drug.
 2. The ocular device defined byclaim 1 wherein the outer membrane material has a release rate to drugand an erosion rate in the eye such that the drug is essentiallydepleted from the inner reservoir prior to the substantially completebioerosion of the membrane material.
 3. The ocular device defined byclaim 1 wherein the drug permeation rate through the inner reservoir isat least twice the permeation rate through the outer membrane.
 4. Theocular device defined by claim 1 wherein the inner reservoir comprises amatrix material selected from the group consisting of solid matrixmaterials and microporous matrix materials having the drug dispersedtherethrough.
 5. The ocular device defined by claim 1 wherein the innerreservoir comprises a hollow container having the drug formulationconfined therein.